title: An intersubunit hydrogen bond in the nicotinic acetylcholine receptor that contributes to channel gating.
abstract: The muscle nicotinic acetylcholine receptor is a large, allosteric, ligand-gated ion channel with the subunit composition alpha2betagammadelta. Although much is now known about the structure of the binding site, relatively little is understood about how the binding event is communicated to the channel gate, causing the pore to open. Here we identify a key hydrogen bond near the binding site that is involved in the gating pathway. Using mutant cycle analysis with the novel unnatural residue alpha-hydroxyserine, we find that the backbone N-H of alphaSer-191 in loop C makes a hydrogen bond to an anionic side chain of the complementary subunit upon agonist binding. However, the anionic partner is not the glutamate predicted by the crystal structures of the homologous acetylcholine-binding protein. Instead, the hydrogen-bonding partner is the extensively researched aspartate gammaAsp-174/deltaAsp-180, which had originally been identified as a key binding residue for cationic agonists.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Kristin Rule
authors.initials: KR
authors.lastname: Gleitsman
authors.forename: Sean M A
authors.initials: SM
authors.lastname: Kedrowski
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D006860:Hydrogen Bonding; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020836:Protein Structure, Quaternary / Q000502:physiology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D007473:Ion Channels; D009124:Muscle Proteins; D011978:Receptors, Nicotinic